Autism and Schizophrenia Genes Show Early, Fleeting Activation

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New research suggests that genes linked to autism and schizophrenia are only switched on during the early stages of brain development, according to a study in mice led by researchers at the University of Oxford. The scientists say their new findings add to the evidence that autism and schizophrenia are neurodevelopmental disorders, meaning that they originate during early brain development.

The researchers studied gene expression in the brains of mice throughout their development, from 15-day old embryos to adults. They focused on cells in the subplate, a region of the brain where the first neurons develop.

“The subplate provides the scaffolding required for a brain to grow, so is important to consider when studying brain development,” says professor Zoltán Molnár, M.D., D.Phil., senior author of the paper. “Looking at the pyramids in Egypt today doesn’t tell us how they were actually built. Studying adult brains is like looking at the pyramids today, but by studying the developing brains we are able to see the transient scaffolding that has been used to construct it.”

The study shows that certain genes linked to autism and schizophrenia are only active in the subplate during specific stages of development. “The majority of the autism susceptibility genes are only expressed in the subplate of the developing mouse brain,” explains Anna Hoerder-Suabedissen, Ph.D., who led the study at the University of Oxford. “Many can only be found at certain stages of development, making them difficult to identify at later stages using previous techniques.”

The team was able to map gene activity in full detail using new methods that allowed them to dissect and profile gene expression from small numbers of cells. This also enabled them to identify the different populations of subplate neurons more accurately.

“I am excited to see tangible genetic links supporting, even indirectly, the idea of a possible role of the transient embryonic subplate zone in the origin of disorders such as autism and schizophrenia,” says Professor Pasko Rakic, M.D., Ph.D., of Yale University, one of the first to discover subplate neurons. “If this is possible to show in mice, where the subplate is relatively small, it is likely to be even more pronounced in humans, where it is much more evolved.

“The study from Professor Molnár’s group at Oxford may be the first step toward finding more such links in the future and opens the possibility of directly examining the roles of genetic variation and exposure to various environmental factors in animal models.”

The research is published today in Proceedings of the National Academy of Sciences in a paper titled “Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia”. The study is a collaboration between researchers from the University of Oxford, King’s College London, and Imperial College London, and was funded by the Medical Research Council and the Wellcome Trust.